Skin cancer is one of the most frequently diagnosed malignancies in the United States, and its incidence has been increasing at an astonishing rate over the past few decades, exceeding the number of all other human cancers combined (Stern, R. S., Arch Dermatol, 2010. 146: p. 279-82). Non-melanoma skin cancer (NMSC) includes basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) and is the most common type of skin cancer with substantial associated morbidity and mortality (Rogers, H. W., et al., JAMA Dermatol, 2015. 151: p. 1081-6). BCCs comprise approximately 80% of skin cancers with SCC as the second most common skin cancer. SCCs are more aggressive and have a higher potential for metastasis compared to BCCs (Samarasinghe, V., et al., Expert Rev Anticancer Ther, 2011. 11: p. 763-9). Solar ultraviolet (SUV) irradiation is well documented as a prominent environmental carcinogen responsible for various physiological and biological effects, including immune suppression, cellular aging, and DNA damage (de Gruijl, F. R., et al., J Photochem Photobiol B, 2001. 63: p. 19-27; and Lopez-Camarillo, C., et al., Int J Mol Sci, 2012. 13: p. 142-72). Furthermore, strong epidemiological and molecular evidence indicates that cumulative exposure to SUV irradiation is the major etiologic factor in the development of NMSC (Burns, E. M., et al., J Skin Cancer, 2013. 2013: p. 246848; Marks, R., Cancer, 1995. 75: p. 607-12; and Sarasin, A., Mutat Res, 1999. 428: p. 5-10). The SUV spectrum can be divided into 3 subtypes according to wavelength and include UVA (320-400 nm), UVB (280-320 nm) and UVC (200-280 nm) (Jung, S. K., et al., Cancer Res, 2008. 68: p. 6021-9). Previous studies indicated that although UVC is filtered out by stratospheric ozone, UVA and UVB each has strong carcinogenic effects on the skin, which can lead to DNA damage, erythema, sunburn, immunosuppression, and, eventually, skin cancer (Lopez-Camarillo, C., et al., Int J Mol Sci, 2012. 13: p. 142-72; Cooper, S. J., et al., Curr Cancer Drug Targets, 2007. 7: p. 325-34; and de Gruijl, F. R., Methods Enzymol, 2000. 319: p. 359-66). Therefore, targeting SUV-induced signaling could be an effective strategy for developing agents for effective chemoprevention and chemotherapy against skin carcinogenesis.
Activation of intracellular signaling pathways in response to SUV irradiation plays a crucial role in SUV-induced skin cancer. The mitogen-activated protein kinases (MAPKs) are serine/threonine protein kinases that are strongly activated by SUV irradiation, and are essential in the regulation of fundamental cellular processes, such as proliferation, differentiation, and apoptosis (Bode, A. M., et al., Sci STKE, 2003. 2003: p. Re2). The MAPK cascades comprise the extracellular signal-regulated kinases (ERKs), p38 MAPKs, and c-Jun NH2-terminal kinases (JNKs). The activation of these pathways occurs rapidly and is vital in the regulation of SUV-induced cellular responses that can lead to skin carcinogenesis (Bode, A. M., et al., Sci STKE, 2003. 2003: p. Re2). T-LAK cell-originated protein kinase (TOPK) is a member of the MEK3/6-related MAPKK family and is highly expressed in many cancers (Zhu, F., et al., Gastroenterology, 2007. 133: p. 219-31). TOPK is an upstream activator of ERKs, p38 MAPKs and JNKs and has been identified as an oncogenic protein that is involved in various cellular functions, such as DNA damage, neoplastic transformation and inflammation (Ayllon, V., et al., Oncogene, 2007. 26: p. 3451-61; Hu, F., et al., Oncogene, 2010. 29: p. 5464-74; and Zykova, T. A., et al., J Biol Chem, 2010. 285: p. 29138-46). Moreover, an accumulation of data provides evidence that the inhibition of TOPK might be useful in cancer chemoprevention and treatment (Kim, D. J., et al., Cancer Res, 2012. 72: p. 3060-8; and Matsuo, Y., et al., Sci Transl Med, 2014. 6: p. 259ra145). However, very few effective TOPK inhibitors have been discovered. Currently, there is a need for agents that are useful for treating cancer. Specifically, there is a need for compounds that inhibit the activity of TOPK.